Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are most useful drugs in the world for the treatment of pain, rheumatic disorders, inflammation, and osteo-arthritis (Harth, M; et al. Br Med J, 1 (5479), 80-83, 1966).
NSAIDs have antipyretic activity and can be used for the treatment of fever. (Koeberle A; et al. Curr Med Chem 16 (32) 2009, 4274-96). So we can not avoid NSAIDs treatment but the major limitation associated with NSAIDs treatment is the development of serious gastropathy or gastric mucosal damage with profuse bleeding and dyspepsia. NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States (Green, G. A., Clin Cornerstone, 3 (5), 50-60, 2001). NSAIDs are also responsible for Nausea/Vomiting, Diarrhea (Simone Rossi, ed (2006). Australian medicines handbook 2006. Adelaide: Australian Medicines Handbook Pty Ltd).
Reference may be made to journal “Maity, P; et al. J Biol Chem, 283 (21), 14391-14401, 2008”, wherein it is well established that the major cause of NSAID-induced gastropathy is the development of oxidative stress in gastric mucosa due to the excess generation of reactive oxygen species (ROS).
It has been documented that ROS induces gastropathy through the induction of both mitochondrial and death-receptor mediated pathway of gastric mucosal cell apoptosis (Maity, P; et al. J Pineal Res, 46 (3), 314-323, 2009). In fact, NSAIDs induce mitochondrial pathology, which is associated with increased generation of intra-mitochondrial ROS, such as O2.−, H2O2 and .OH leading to oxidative stress. O2.− is the most effective to damage mitochondrial aconitase, leading to the release of iron from its iron-sulfur cluster. The released iron, by interacting with intra-mitochondrial H2O2 forms .OH. Interestingly, intra-mitochondrial .OH generation is crucial for the development of mitochondrial pathology and activation of mitochondrial death pathway by indomethacin (Maity, P.; et al. J. Biol. Chem. 284:3058-3068; 2009). Chelation of free iron by desferrioxamin or prevention of the oxidative stress in gastric mucosa can protect gastric mucosal damage (Bandyopadhyay et al. Life Sci. 2002 Nov. 1; 71(24):2845-65). The release and involvement of serotonin (5-hydroxytryptamine) in gastric mucosa (Ogihara, Y; et al. Jpn J Pharmacol, 61 (2), 123-131, 1993) is also evident in NSAID-induced gastric mucosal injury. Serotonin (5-hydroxy tryptamine) is a biogenic amine and well known neurotransmitter (Kushnir I H; et al. Fiziol Zh, 55 (3), 125-127, 2009).
It is important to mention that serotonin reduces gastric mucosal blood flow (GMBF) by vasoconstriction and thereby causing acute gastric injury (Wong, S. H; et al. Digestion, 45 (1), 52-60, 1990, Yoneda, M; et al. Am J Physiol, 269 (1 Pt 2), R1-6, 1995) through the generation of ROS by promoting ischemia (Khan, M; et al. J Pharmacol Exp Ther, 323 (3), 813-821, 2007). Serotonin adversely affects the defense mechanisms of the gastric mucosa by reducing the secretory function of the mucosal cells and to weaken the epithelial and vascular integrity. Neutrophil activation appears to be responsible for the detrimental effects of 5-HT partly through the elevation in myeloperoxidase (MPO) activity (Ko, J; et al. Free Radic Biol Med, 24 (6), 1007-1014, 1998).
It is worth mentioning that serotonin plays an important role in indomethacin, [non-steroidal anti-inflammatory drug (NSAID)], ethanol (Wong, S. H; et al. Digestion, 45 (1), 52-60, 1990) and stress-induced gastric ulcer (Debnath, S; et al. Indian J Exp Biol, 45 (8), 726-731, 2007). Serotonin can cause oxidative stress through the generation of ROS (Bianchi, P; et al. FASEB J, 19 (6), 641-643, 2005). Serotonin is released in response to inflammation (Yoneda, M; et al. Am J Physiol, 269 (1 Pt 2), R1-6, 1995) and the increase in mucosal XO activity by serotonin may induce free radical production and possibly modulate the ulcerogenic processes (Ko, J; et al. Free Radic Biol Med, 24 (6), 1007-1014, 1998). Serotonin generates ROS by receptor-independent and receptor-dependent mechanisms (Bianchi, P; et al. FASEB J, 19 (6), 641-643, 2005). Gastric ulcer or gastropathy is a kind of inflammatory disorder of gastric mucosa (Mierzwa, G; et al. Med Wieku Rozwoj, 9 (4), 647-654, 2005).
Thus, it will be of great benefit to synthesize molecule, which will scavenge ROS or chelate free iron and at the same time will prevent the interaction of serotonin with its corresponding receptor to combat NSAID-induced gastropathy or related disorders. Gallic acid (GA), an iron chelator, is a gastroprotective compound and efficiently protects NSAIDs-induced gastric mucosal damage (Pal, C; et al. Free Radic Biol Med, 49(2), 258-267; 2010). The mechanistic studies reveal that GA offers gastroprotective effect by preventing the NSAID-induced mitochondrial oxidative stress and apoptosis in gastric mucosal cells and it also prevents the NSAID-induced mitochondrial dysfunction (Pal, C; et al. Free Radic Biol Med, 49(2), 258-267; 2010).
Present invention provides different tryptamine (serotonin like molecule) derivatives by formation of amide or ester linkage with GA and some other tryptamine derivatives by replacing GA with some other known antioxidant such as 4-hydroxy cinnamic acid, 3-indole acetic acid. The major disadvantage of serotonin is its toxicity. On the other hand the limitation of GA is its poor bioavailability (Shahrzad, S; et al. J Nutr, 131 (4), 1207-1210, 2001). Pharmacokinetics and bioavailability studies indicate that GA is metabolized into 4-O-methylgallic acid very rapidly and the bioavailability in plasma is low. The 38% of the intake of GA were excreted through urine (Shahrzad, S; et al. J Nutr, 131 (4), 1207-1210, 2001, Manach, C; et al. Am J Clin Nutr, 81 (1 Suppl), 230S-242S, 2005). indole-3-acetic acid and 4-hydroxy cinnamic acid plays an important antioxidant activity by scavenging free radical (Cano, A; et al Anal Bioanal Chem (2003) 376: 33-37, Kylli, P; Anal Bioanal Chem (2003) 376: 33-37). It has been reported that the serotonin derivative (compound 2b of the present study) can be biosynthesized by the combination of serotonin and 4-hydroxycinnamic acid by serotonin N-hydroxycinnamoyl transferase (SHT) (Kiyoon Kang et al, Appl Microbiol Biotechnol (2009) 83:27-34). It was isolated from the seeds of Centaurea montana (Asteraceae), and it shows in vitro cytotoxic activity against the CaCo2 colon cancer cells (Mohammad Shoeb et al, Tetrahedron 62 (2006) 11172-11177).
There are some limitations of the existing gastro protective compounds such as proton pump inhibitors (omeprazole, lansoprazole. etc), H2 receptor blockers (ranitidine, cimetidine etc). Although these existing molecules are effective at a very low dose against NSAID-induced gastropathy but it has some adverse effects like diarrhea (Mukherjee, S., J Gastroenterol Hepatol, 18 (5), 602-603, 2003), linear mucosal defects and friable mucosa associated with collagenous colitis, leydig cell tumors, subacute cutaneous lupus erythematosus, myopathy including polymyositis, acute nephritis and anaphylactic reactions (Mukherjee, S., J Gastroenterol Hepatol, 18 (5), 602-603, 2003, Clark, D. W; et al. Fundam Appl Toxicol, 26 (2), 191-202, 1995). Proton pump inhibitors are reported to be associated with an increased risk of bacterial infection and related diseases (Dial, S; et al. JAMA, 292 (16), 1955-1960, 2004).
The synthesized derivatives of the present invention have several advantages. These derivatives can chelate free iron, prevent oxidative stress by scavenging ROS and simultaneously offer antiapoptotic effect in vitro. These derivatives have the ability to prevent the formation of iron-mediated .OH as well as scavenge ROS in vivo. These derivatives can prevent gastric mucosal oxidative stress and gastropathy by preventing ROS-mediated activation of apoptosis in gastric mucosal cells induced by NSAIDs.